Dimeric natural product panepocyclinol A inhibits STAT3 <i>via</i> di-covalent modification.

Li LI; Yuezhou WANG; Yiqiu WANG; Xiaoyang LI; Qihong DENG; Fei GAO; Wenhua LIAN; Yunzhan LI; Fu GUI; Yanling WEI; Su-Jie ZHU; Cai-Hong YUN; Lei ZHANG; Zhiyu HU; Qingyan XU; Xiaobing WU; Lanfen CHEN; Dawang ZHOU; Jianming ZHANG; Fei XIA; Xianming DENG

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Dimeric natural product panepocyclinol A inhibits STAT3 via di-covalent modification.

Author: Li LI ¹ ; Yuezhou WANG ¹ ; Yiqiu WANG ² ; Xiaoyang LI ¹ ; Qihong DENG ¹ ; Fei GAO ¹ ; Wenhua LIAN ¹ ; Yunzhan LI ¹ ; Fu GUI ¹ ; Yanling WEI ¹ ; Su-Jie ZHU ³ ; Cai-Hong YUN ³ ; Lei ZHANG ¹ ; Zhiyu HU ¹ ; Qingyan XU ¹ ; Xiaobing WU ¹ ; Lanfen CHEN ¹ ; Dawang ZHOU ¹ ; Jianming ZHANG ⁴ ; Fei XIA ² ; Xianming DENG ¹
Author Information

1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
2. School of Chemistry and Molecular Engineering, NYU-ECNU Center for Computational Chemistry at NYU Shanghai, East China Normal University, Shanghai 200062, China.
3. Department of Biochemistry and Biophysics, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
4. Institute of Translational Medicine & Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 201203, China.
Publication Type:Journal Article
Keywords: Anaplastic large T cell lymphoma; Di-covalent modification; Dimeric compounds; Dimerization; Natural product; Panepocyclinol A; STAT3 inhibitor; Signal transducer and activator of transcription 3
From: Acta Pharmaceutica Sinica B 2025;15(1):409-423
CountryChina
Language:English
Abstract: Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.